Cross-diagnostic genetic organization of clinical readouts corresponds to distributed cortical profiles.

Abstract

Psychiatric disorders share common-variant liability, and the Psychiatric Genomics Consortium has identified five correlated cross-disorder genetic dimensions derived from diagnoses. Whether these dimensions also organize heterogeneous clinical observations and their cortical associations remains unclear. We used F1-F5, together with hierarchical p, as external coordinates for 37 genetically informative clinical readouts and integrated them with structural-imaging GWAS. Thirty-one readouts showed multidimensional profiles, although Internalizing was strongest for most. Racing thoughts illustrated this organization, spanning four dimensions and showing, in a separate imaging analysis, a bounded association with right frontal-pole gray-matter volume. Broad psychopathology, several clinical readouts, and distributed cortical regions converged on a common pattern: inverse associations with cortical surface area. Beyond individual regions, readouts with more similar five-coordinate profiles also had more similarly shaped cortical association maps across 34 regions. We then asked whether coordinate-based projections could recover the collective cortical organization without using the observed readout-cortex cells in their construction. They recovered part of this organization and preserved part of its pairwise geometry. Hierarchical p also corresponded with parts of these fields. Together, these findings suggest that diagnosis-derived genetic structure provides a bridge between heterogeneous clinical readouts and distributed cortical morphology, without reducing either to single diagnoses or single brain regions.